PROJECT SUMMARY: Foamy viruses (FVs) are integrating retroviruses with many properties that distinguish them from gammaretroviruses or lentiviruses; one important characteristic for gene therapy applications is that FV are nonpathogenic. FV vectors have improved from early replication competent vectors to advanced vectors that do not contain detectable replication competent retroviruses. Importantly, with the exception of persons exposed to primates, FV vectors do not infect humans, and uninfected humans do not have antibodies to FV vectors, which makes them also ideal vectors for in vivo delivery. FV vectors can transduce pluripotent murine and human repopulating cells, and for human CD34+ repopulating cells this was unequivocally demonstrated by sequencing and identifying identical FV vector integration sites in repopulating myeloid and lymphoid cells. Significant silencing of vector transgenes in either murine or human repopulating cells was not observed in these studies. Importantly, FV vectors efficiently transduce long-term repopulating hematopoietic stem cells (HSC) in the canine large animal model with high levels of marked granulocytes and lymphocytes. Thus, FV vectors are potentially the best currently available vector system for the correction of genetic diseases like SCID-X1. Dr. Kiem has extensive experience with the development and generation of new vector systems. He has studied gammaretrovirus, lentivirus and FV vectors in large animal models and is, therefore, very familiar with large-scale vector production and experiments conducted in large animals like dogs. Dr. Kiem has also significant expertise in clinical vector production and gene therapy studies. The FHCRC has a fully established cGMP facility for clinical grade vector production. Core B will provide the following resources to all 3 Projects within this application: 1)Provision of FV Vectors, 2) Optimization of FV vector production and 3) Clinical GMP-grade FV vector production.